Cannibalism constitutes a consumption strategy used by micro- and higher organisms to adapt to environmental stresses and to survive. Gram positive species, Bacillus subtilis and Streptococcus pneumonia exert cannibalistic activities during the early stages of sporulation (Gonzalez-Pastor et al., Science 2003) or during natural genetic transformation (Guiral et al., PNAS 2005). In contrast, the slime molde Dictyostelium caveatum represses its predatory abilities during its quasi-multicellular differentiation stage (Waddell and Duffy, The Journal of cell biology 1986). In Drosophila, studies on genetic mosaics that place cells in competition within tissues unrevealed that cannibalism is a genetically controlled process that may occur at the single cell level and actively participates to cell competition during tissue repair and tumor development (Li and Baker, Cell 2007). Although cellular cannibalism is poorly reported in physiological situations, cannibal cells have been frequently detected in various human tumor types such as melanoma, leukemia and cervical carcinoma, colon carcinoma, stomach carcinoma, liver carcinoma adenocarcinoma and in metastatic breast carcinoma (Overholtzer and Brugge, Nature reviews Molecular cell biology 2008).
On a one hand, cellular cannibalism was suggested to cause the destruction of cancer cells by other malignant cells by entosis. In contrast to other (apoptotic, necrotic or autophagic) cell death forms that are controlled in a cell-autonomous fashion, entosis (from the Greek word entos, which means inside, into, or within) requires the internalization of a live <<target>> cancer cell by a live <<cannibal>> cancer cell (Overholtzer and Brugge, Nature reviews Molecular cell biology 2008). An inverse correlation between entosis and metastasis appearance in human pancreatic adenocarcinoma was furthermore reported, suggesting that this atypical death process may represent an intrinsic tumor suppression mechanism (Cano et al., EMBO Mol Med. 2012).
On another hand, cellular cannibalism was shown to provoke the polyploidization of the engulfing cell by disrupting cytokinesis, and hence to promote oncogenesis indirectly, by generating polyploid cells that tend to generate aneuploidy daughter cells (Krajcovic et al., Nat Cell Biol. 2011; Krajcovic and Overholtzer, Cancer Res. 2012).
As a consequence of (homotypic or heterotypic) interactions between cancer cells or between cancer cells and other (stromal or immune) cells, cannibalism could have—depending on the genetic status of cancer cells (target and cannibal cells) and on tumor microenvironment—variable consequences on tumor growth and disease outcomes.
Although the “cell-in-cell” cytological features have been widely reported in human tumors, the molecular and cellular bases of cellular cannibalism remain unknown.
In this context, the present inventors provide evidence that TP53 and, more specifically, Δ133TP53, acts as repressors of cellular cannibalism. Their results also unrevealed that cellular cannibalism is functionally connected to senescence, both in vitro (in cellular models of senescence) and in vivo (in human breast carcinoma), where they may influence the efficiency of a chemotherapeutic treatment.